SUNDAY - January 27, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

N-myc Gene’s Role in Retinal Development

A genetic discovery led by scientists at St. Jude Children’s Research Hospital helps answer a long-standing mystery about the eyes of vertebrates, and may translate into a deeper understanding of how genes coordinate the complex process of eye formation and how a rare pediatric eye cancer progresses.

“A series of complex developmental processes must be carefully orchestrated for the eye to form correctly,” said Michael Dyer, Ph.D., associate member in the St. Jude Department of Developmental Neurobiology. “One important aspect of this coordination is that retinal thickness be the same, irrespective of eye size. For example, the mouse eye is about 5,000 times smaller than that of the elephant eye, but the retinal thickness in these two species is comparable.”

Genes in the Myc family carry out vital roles during prenatal development by regulating the proliferation, size, differentiation and survival of cells. Myc genes are also proto-oncogenes - genes in which a mutation enables them to transform normal cells into cancerous ones. Malfunctioning N-myc genes are often associated with pediatric neural cancers, including neuroblastoma, medulloblastoma and retinoblastoma.

“The determination of N-myc target genes during retinal development may also contribute to the current understanding of retinoblastoma progression,” he said.

The researchers discovered that N-myc is not involved in regulating cell survival or neuronal differentiation in the developing retina. But, the gene is crucial for the proper proliferation of retinal cells. In mice in which the scientists inactivated N-myc, the volume of the retina was significantly smaller than in mice with normally functioning N-myc.

The researchers hypothesize that N-myc’s activity occurs early in the cascade of reactions that control development of the retina and other eye components. Therefore, when something inactivates the gene, the result is both a reduction in retinal progenitor cell proliferation and a reduction in the signaling cues that coordinate the growth of the eye and retina.

“Importantly, for retinas to maintain nearly constant thickness across species that have different sizes of eyes, the total number of retinal cells must change several-fold,” Dyer said. “The identification of N-myc as a key regulator of these processes allows us to begin to understand the coordination of complex developmental programs in the developing eye and how these processes have evolved.”

Published January 15, 2008 by the journal Genes and Development
return to top of page


Researchers Determine Structure of Protein Involved in Spastic Paraplegia

Spastin functions as a microtubule dismantler, remodeling the network of microscopic conduits that transport molecules around cells. The first atomic resolution structure of spastin, suggests that it functions by slurping up a segment of the microtubule protein into a central pore, and then a set of molecular ratchets pulls upon the microtubule until it eventually breaks.

Mutations in spastin have been implicated in hereditary spastic paraplegias (HSPs), a group of disorders characterized by progressive weakness and stiffness in the legs that can lead to complete loss of function. The disease, which affects about 20,000 people in the United States, can also cause mental retardation and abnormalities of the retina and skin. Despite evidence that spastin plays a role in HSPs, however, “the biology of the protein and the cellular pathological of the disease is still very mysterious,” said Ronald Vale, an HHMI investigator at the University of California, San Francisco, who led the study.

One theory, said Vale, is that spastin might be breaking apart microtubules as part of an ongoing process of microtubule network “remodeling.” If microtubule remodeling is inhibited in some of the body's longest nerve cells due to a loss of spastin function, said Vale, the result might eventually lead to spastic paraplegias.

From previous studies and comparison with similar proteins, Vale and Roll-Mecak suspected that spastin is actually a group of six identical enzyme subunits, linked in a ring, that use energy derived from hydrolyzing the small molecule ATP to break the microtubule. To probe exactly how this occurred, the researchers obtained the protein from the fruit fly Drosophila and the worm C. elegans, and used two different x-ray techniques to determine the structure of the intact enzyme, as well as a single spastin subunit.

They obtained detailed structures, as well as functional tests of spastin-mediated severing in a test tube, offer a new view of how spastin grabs and severs microtubules. “Spastin appears to grab a loose tail region of the microtubule and mechanically ratchet it through the pore, a kind of noodle-slurping mechanism used by other ring-shaped enzymes that are close relatives of spastin. We also find that some microtubules in neurons might be more susceptible to these actions of spastin than others” said Vale.

Vale and Roll-Mecak's study pinpointed the exact location of diseasing-causing mutations, thus revealing how changes in spastin's structure might cause HSP.

Significantly, different spastin mutations found in patients with HSP interfere with distinct steps in the microtubule-severing process. For example, Vale said, some mutations most likely affect spastin's ability to pull microtubules through its core, while others affect binding of the energy-containing molecule ATP. Still others seem to block spastin's ability to form its six-membered ring structure.

“With this structure, we can pinpoint a number of different kinds of ways in which these disease mutations interfere with the function of this protein,” he said. Further work is needed, he noted, to link the findings directly to spastin's role in human disease. “While this structure has given us important insights into spastin's structure and mechanism, we have just scratched the surface in understanding this protein,” he said. “We still need to understand whether spastin is performing the same kind of reaction in the living neuron that we see in the test tube,” he said.

Published January 17, 2008 in the journal Nature
return to top of page


Marijuana Withdrawal as Bad as Withdrawal From Cigarettes

Research by a group of scientists studying the effects of heavy marijuana use suggests that withdrawal from the use of marijuana is similar to what is experienced by people when they quit smoking cigarettes. Abstinence from each of these drugs appears to cause several common symptoms, such as irritability, anger and trouble sleeping - based on self reporting in a recent study of 12 heavy users of both marijuana and cigarettes.

“These results indicate that some marijuana users experience withdrawal effects when they try to quit, and that these effects should be considered by clinicians treating people with problems related to heavy marijuana use,” says lead investigator in the study, Ryan Vandrey, Ph.D., of the Department of Psychiatry at the Johns Hopkins University School of Medicine.

Marijuana is the most widely used illicit drug in the United States. Admissions in substance abuse treatment facilities in which marijuana was the primary problem substance have more than doubled since the early 1990s and now rank similar to cocaine and heroin with respect to total number of yearly treatment episodes in the United States, says Vandrey.

Since the drafting of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, (DSM-IV) in 1994, an increasing number of studies have surfaced suggesting that cannabis has significant withdrawal symptoms. What makes Vandrey’s recent study unique is that it is the first study that compares marijuana withdrawal symptoms to withdrawal symptoms that are clinically recognized by the medical community - specifically the tobacco withdrawal syndrome.

Vandrey’s study, which appears in the January issue of the journal Drug and Alcohol Dependence, followed six men and six women at the University of Vermont in Burlington and Wake Forest University School of Medicine in Winston-Salem, N.C., for a total of six weeks. All were over 18 (median age 28.2 years), used marijuana at least 25 days a month and smoked at least 10 cigarettes a day. None of the subjects intended to quit using either substance, did not use any other illicit drugs in the prior month, were not on any psychotropic medication, did not have a psychiatric disorder, and if female, were not pregnant.

Results showed that overall withdrawal severity associated with marijuana alone and tobacco alone was of similar frequency and intensity. Sleep disturbance seemed to be more pronounced during marijuana abstinence, while some of the general mood effects (anxiety, anger) seemed to be greater during tobacco abstinence. In addition, six of the participants reported that quitting both marijuana and tobacco at the same time was more difficult than quitting either drug alone, whereas the remaining six found that it was easier to quit marijuana or cigarettes individually than it was to abstain from the two substances simultaneously.

Vandrey recognizes that the small sample size is a limitation in this study, but the results are consistent with other studies indicating that marijuana withdrawal effects are clinically important.

Published January 24, 2008 in the journal Drug and Alcohol Dependence.
return to top of page


SATURDAY - January 26, 2008-----------------------------------------------News Archive/Return to Today's News Alerts

Scientists Synthesize a Genome From Scratch

Researchers have rebuilt an entire genome from scratch, they report in Science. Although the team has yet to demonstrate that this DNA can substitute for the real thing, the work paves the way for customized bacteria that could efficiently produce drugs, biofuels, and other molecules useful to humankind.

Ever since his group decoded the genome of Mycoplasma genitalium, a parasitic bacterium that lives in the human urogenital tract, sequencing maverick J. Craig Venter has wanted to remake the bug's genome in the lab. At just under 600,000 bases, M. genitalium sports the smallest known genome for a free-living organism, and Venter hoped that an artificial genome could be modified to turn the bacterium into a living chemical-manufacturing plant.

Last year, Venter and his colleagues developed a technique for replacing M. genitalium's genome with another natural genome from a different species (Science, 3 August 2007, p. 632). But synthesizing the M. genitalium genome from the ground up proved challenging, in part because long strands of DNA are quite fragile.

Japanese researchers have built a large genome from two existing bacterial chromosomes. But Venter, Hamilton Smith, and their colleagues at the J. Craig Venter Institute in Rockville, Maryland, started with short pieces of DNA that a company had manufactured base by base. About 6000 bases long, these pieces represented overlapping bits of the microbe's only chromosome. Some of the pieces also contained "watermarks": a few extra or different bases here and there that distinguish an artificial chromosome from a natural one.

To link the pieces, Smith and Venter's team used enzymes that allowed them to join longer and longer DNA strands until they had just four, each representing one-quarter of the genome. Finally, the team inserted these quarters into yeast, which copied and combined them into a complete chromosome.

The researchers sequenced their newly constructed genome and, except for the watermarks, it matched M. genitalium's exactly. The work is "a technical tour de force" and a "monumental effort," says yeast biologist Jef Boeke of Johns Hopkins University School of Medicine in Baltimore, Maryland.

However, to be sure this genome works as it should, the researchers must still put it into a DNA-less M. genitalium, notes Eckard Wimmer, a molecular virologist at Stony Brook University in New York state: "Proof is biological function, and that's missing in this paper."

Published January 24, 2008 in the journal Science.
return to top of page


International Team to Sequence 1000 Genomes

Just a year after the first individual human genomes were sequenced, an international team announced that it will probe the entire genomes of about 1000 people. The aim is to create the most detailed catalog yet of human genetic diversity to help biomedical researchers home in on disease genes.

The 1000 Genomes Project will delve much deeper than the three celebrity genomes completed last year, including those of genome researcher J. Craig Venter and DNA co-discoverer James Watson (ScienceNOW, 4 September 2007). It will build on the recently completed HapMap, which describes how blocks of DNA tagged by common variants, called single-nucleotide polymorphisms (SNPs), vary in different populations (ScienceNOW, 26 October 2005).

These SNPs have turned up more than 100 new DNA markers associated with common illnesses such as diabetes and heart disease (Science, 21 December 2007, p. 1842). But the HapMap includes only the most common markers, those present in at least 5% of the population.

To find rarer SNPs that occur at 1% frequency, genome leaders say, they need to sequence about 1000 genomes. The 3-year project, which will cost $30 million to $50 million, will take advantage of new technologies that have slashed the cost of sequencing. The work will be funded by the U.S. National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, the Sanger Institute in Hinxton, U.K., and the Beijing Genomics Institute in Shenzhen, China.

The consortium will start with three pilot projects. One will exhaustively sequence the entire genome of six individuals: two adults and both sets of their parents.

A second project will sequence 180 individual genomes at light coverage, leaving gaps.

The third project will fully sequence the protein-coding regions of 1000 genes (5% of the total) in about 1000 genomes. The samples, all anonymous and with no clinical information, will mainly be drawn from those collected for the HapMap, which includes people of European, Asian, and African descent. The first data from the pilot projects should become public later this year.

The new catalog could help disease gene hunters in several ways. It will potentially eliminate the need to sequence around a newly discovered disease SNP to find the variant that actually alters the gene product, says NHGRI Director Francis Collins.

The project will also catalog genes that are sometimes lost or duplicated - such copy-number variants can cause disease. By compiling rarer variants, the project should also help resolve a debate about the relative contribution of these mutations to disease risks. Most disease SNPs found so far raise risk only 50% or less, for example, and some researchers suspect that there are rarer SNPs that raise risk twofold, threefold, or more.

"There's no question it's going to be a tremendous resource," says Yale University's Judy Cho, who has used the HapMap to find a new gene for Crohn's disease.

Published January 22, 2008 by the National Human Genome Research Institute
return to top of page


Protein That Controls Hair Growth Also Keeps Stem Cells Slumbering

Like fine china and crystal, which tend to be used sparingly, stem cells divide infrequently. It was thought they did so to protect themselves from unnecessary wear and tear. But now new research from Rockefeller University has unveiled the protein that puts the brakes on stem cell division and shows that stem cells may not need such guarded protection to maintain their potency.

This research raises questions about what stem cells need in order to maintain their ability to regenerate tissue. It may also be key in developing new treatments for thinning hair.

The impetus for the work began five years ago when Elaine Fuchs, head of the Laboratory of Mammalian Cell Biology and Development, and several researchers in her lab discovered that the protein NFATc1 was one of only a few that are highly expressed within the stem cell of the hair follicle. Clinical research, meanwhile, showed that the immunosuppressant that inhibits NFATc1, a drug called cyclosporine A, has a rather unsightly side effect: excessive hair growth.

Fuchs and Valerie Horsley, a postdoc in her lab, realized the connection between the drug’s side effect and the abundance of NFATc1 within the hair follicle’s stem cell compartment — the bulge. The mice they treated with the drug grew fur at a much faster rate than mice they did not treat. They showed that this excessive hair growth was due to increased stem cell activity within the bulge, a process that cranked up the production of hair by shifting the cell cycle from its resting phase, when stem cells slumber, to its growth phase, when stem cells proliferate.

“It seems like the resting phase isn’t as necessary as was once thought,” says Horsley. “Even though these stem cells are highly proliferative, they still maintain their stem cell character.”

In probing the underlying mechanisms mediating this process, Horsley and Fuchs discovered that NFATc1, a transcription factor, blocks the expression of a gene that provides the cell cycle with “go ahead” signals at certain checkpoints. By blocking these signals, NFATc1 prevents the stem cells from dividing, preventing unnecessary wear and tear. These same cells, if treated with cyclosporine A, show a rapid loss of the transcription factor, an effect that turns "on" at these checkpoints.

So far, these proliferating stem cells lacking NFATc1 have not led to increased tumor formation, which is often a dangerous byproduct of triggering stem cells into action. “This is the first case where we have been able to activate the hair cycle without accompanying signs of tumorigenesis,” says Fuchs.

Because the current study was observational in nature, it could only reveal associations.

Published January 25, 2008 in the journal Cell
return to top of page

FRIDAY - January 25, 2008-----------------------------------------------News Archive/Return to Today's News Alerts

Elusive Pancreatic Stem Cells Found In Adult Mice

Just as many scientists had given up the search, researchers have discovered that the pancreas does indeed harbor stem cells with the capacity to generate new insulin-producing beta cells.

If the finding made in adult mice holds for humans, the newfound progenitor cells will represent "an obvious target for therapeutic regeneration of beta cells in diabetes.

"One of the most interesting characteristics of these [adult] progenitor cells is that they are almost indistinguishable from embryonic progenitors," said Harry Heimberg of the JDRF Center at Vrije Universiteit Brussel in Belgium and the Beta Cell Biology Consortium. "In terms of their structure and gene expression, there are no major differences. They look and behave just like embryonic beta cell progenitors."

Insulin is required for cells to take up blood sugar, the body's primary energy source. In people with certain types of diabetes, blood sugar rises due to an inability of pancreatic beta cells to produce insulin in sufficient quantities.

Previous studies had failed to demonstrate the existence of bona fide beta cell progenitors in the pancreas after birth. "Most people gave up looking because they are so few and so hard to activate," Heimberg said.

In the new study, Heimberg's team tied off a duct that drains digestive enzymes from the pancreas. That injury led to a doubling of beta cells in the pancreas within two weeks, they showed. The animals' pancreases also began producing more insulin, evidence that the new beta cells were fully functional, Heimberg said. He suspects the regenerative process is sparked by an inflammatory response in the enzyme-flooded pancreas.

They further found that the production of new beta cells depends on a gene called Neurogenin 3 (Ngn3), which is known to play a role in the pancreas during embryonic development.

"The most important challenge now is to extrapolate our findings to patients with diabetes," Heimberg said. Although he cautioned that any potential diabetes treatment remains far into the future, "our findings reveal the significance of investigating the feasibility of (1) isolating facultative beta cell progenitors and newly formed beta cells from human pancreas in order to expand and differentiate them in vitro and transplant them in diabetic patients and (2) composing a mix of factors able to activate beta cell progenitors to expand and differentiate in situ in patients with an absolute or relative deficiency in insulin."

Published January 25, 2008 in the journal Cell.
return to top of page


Experimental Procedure Induces Tolerance to Mismatched Kidney Transplants

Four of five patients participating in a trial of an experimental protocol designed to induce immune tolerance to HLA-mismatched kidney transplants have been able to discontinue immunosuppressive drugs.

A mismatch of HLA (human leukocyte antigen) proteins is the most difficult immunological barrier to transplantation. The report of the study conducted at Massachusetts General Hospital (MGH).

"We are very encouraged by our initial success in inducing tolerance across the HLA barrier, something that has been a major goal of transplant immunology for years," says David H. Sachs, MD, director of the MGH Transplantation Biology Research Center, the study's senior author. "While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced."

For more than three decades, Sachs and his colleagues have been pursuing ways to induce tolerance, tricking the immune system into regarding a donor organ as "self." Over the years the team has developed an approach in which the organ recipient receives bone marrow from the donor along with the needed organ to produce a state called mixed chimerism, an immune system that blends elements of both the donor and recipient.

The current study enrolled five patients whose kidney failure resulted from non-cancerous conditions and who did not have an HLA-matched living donor. The study protocol begins with therapy designed to partially destroy the recipient's bone marrow and treatment with an antibody that reduces the level of T cells, the immune system component primarily involved in organ rejection. After receiving the transplanted kidney and bone marrow, patients stay in a relatively sterile environment for about two weeks, allowing the bone marrow to regenerate and produce new immune cells that are tolerant of the donor organ.

The first two patients in the trial were successfully weaned from immunosuppressive drugs in the months following their transplant, but the third patient developed early rejection and eventual failure of the donor kidney. Since the antidonor immune response of that patient - who subsequently received a successful second transplant with conventional immunosuppression - was primarily caused by the immune system's B cells, the study protocol was adjusted to include an additional antibody targeting B cells. The fourth and fifth patients, both of whom received the revised protocol, were able to discontinue immunosuppressives 8 and 10 months after their tranplants. All four of the successfully transplanted patients continue to have normal kidney function from two to more than five years later.

As seen in previous animal studies and in some of the myeloma patients receiving matched transplants, the chimeric state - the presence in bone marrow of immune cells from both recipient and donor - was temporary, even though tolerance to donor tissue continues. Sachs and his colleagues are continuing to investigate this phenomenon, which they believe may involve some factor provided by the donor organ. "We have shown in monkeys that the kidney itself is required to maintain this state that we call peripheral tolerance, although we still don't fully understand the mechanism," he explains.

The stem cells are infused into the transplant recipient via an IV five days after surgery. The next stem cell transfusion is about three months after surgery, then six months and finally nine months after the transplant. The recipient is treated with Campath-1H, a potent antibody used extensively at Northwestern to prevent rejection, in addition to other standard anti-rejection medications. About a year after surgery, the subject is weaned off of one anti-rejection drug, then another, while undergoing tests to ensure the transplant is still going well.

Published January 24, 2008 in the New England Journal of Medicine
return to top of page


Large Study Links Folic Acid Supplementation With Reduced Risk Of Preeclampsia During Pregnancy

Folic acid supplementation during pregnancy has long been known to reduce the risk of birth defects in newborns, but a new study now suggests that the vitamin may also reduce the risk of preeclampsia, a leading cause of maternal and infant illness and death worldwide.

As described in the January 2008 issue of the American Journal of Obstetrics and Gynecology, researchers closely followed approximately 3,000 pregnant women at The Ottawa Hospital and the Kingston General Hospital and found that preeclampsia occurred in 2.2 per cent of women who took multivitamins containing folic acid compared to 5.1 per cent of women who did not.

The study was purely observational and women were not asked to make any changes to their daily lifestyle or health care. Known preeclampsia risk factors such as maternal age, education level and previous preeclampsia were controlled for and the difference was found to be significant by conventional standards.

Because of the known association of folic acid and reduced risk of birth defects, Health Canada currently recommends that all pregnant women take 0.4 mg folic acid per day while the Society of Obstetricians and Gynaecologists of Canada recommends a dose of 1 mg per day. In the current study, 92 per cent of women were taking folic acid, mostly at the higher dose.

Preeclampsia is characterized by high maternal blood pressure and urine protein – conditions that increase the risk of stroke, kidney problems, premature birth and other complications. There are currently no established treatments to prevent preeclampsia or lessen its effects.

“Previous smaller observational studies had suggested a link between folic acid and reduced risk of preeclampsia, but our study is the largest yet to test this association, and it was very carefully designed,” said lead author Dr. Shi Wu Wen, a Senior Scientist at the Ottawa Health Research Institute and Professor at the University of Ottawa.

“The data also makes sense from a biological standpoint, because we know that folic acid has an important role in the development and function of blood vessels, and increasing evidence suggests that this process is disrupted in women with preeclampsia.”

Because the current study was observational in nature, it could only reveal associations.

Published January, 2008 in the American Journal of Obstetrics and Gynecology
return to top of page


THURSDAY - January 24, 2008-----------------------------------------------News Archive/Return to Today's News Alerts

Key Bone Building Pathway Identified in Mice

Researchers at the San Francisco VA Medical Center, University of California, San Francisco, and Gladstone Institute of Cardiovascular Disease have uncovered a biochemical signaling pathway that leads to the formation of abnormally large bones in mice.

For humans, the discovery may provide clues to both childhood bone formation and osteoporosis – the loss of bone in old age – as well as a path to improved osteoporosis treatments.

“We’re trying to understand how signaling pathways control bone mass and bone quality,” says senior investigator Robert A. Nissenson, PhD, a senior research scientist at SFVAMC and a professor of medicine and physiology at UCSF. “This is critical, since the major defect that occurs in osteoporosis is a deficit in the amount and quality of bone.”

The researchers used a strain of genetically engineered mouse in which a specially designed hormone receptor activates a signaling pathway called Gs, which is known to affect bone growth. They found that the mice with continuously active Gs signaling in bone developed abnormally large and misshapen bones by the age of nine weeks.

“The bones were four to six times larger in cross section than normal – an absolutely astonishing effect,” says Nissenson.

The Gs pathway is clinically significant because in osteoblasts – the cells that create and maintain bone – it is normally activated by administration of parathyroid hormone (PTH), which is commonly used as a treatment for osteoporosis.

“In humans, PTH has to be given as a daily injection, and does not result in a very large increase in bone mass,” notes lead author Edward C. Hsiao, MD, PhD, a California Institute of Regenerative Medicine Scholar at the Gladstone Institute of Cardiovascular Disease and an endocrinology fellow at UCSF. “For treating osteoporosis, it would be desirable to optimize this process in order to improve the rate of bone formation.”

Intriguingly, the researchers observed that when the Gs–activating receptor was kept turned off in the mice until the age of four to six weeks – when mice reach puberty – and then turned on, bone development was normal.

"“This suggests that for this particular receptor, there’s a crucial window of time in terms of how and when its activation affects bone growth and development,” says Hsiao.

“For humans, clinically speaking, this could be very important,” Nissenson observes. “Susceptibility to fracture in old age is directly related to bone mass, which reaches a peak at age 30 or so and then slowly declines. If this signaling system could somehow be manipulated in youth, it could be a way of reducing fracture risk later in life.”

Hsiao cautions that the excess bone formed in the mice is an abnormal type called trabecular bone, which unlike normal skeletal bone is spongy, soft, and lacks a hard outer shell called the cortex. “This is not the ideal type of bone you’d want to grow to treat osteoporosis,” he says. “On the other hand, this shows that we are able to increase bone mass using cells already present in the animal. It’s possible that by tweaking other systems, we can stimulate the growth of normal skeletal bone.”

Published January 22, 2008 in the PNAS - Proceedings of the National Academy of Sciences
return to top of page


Northwestern Memorial Transplant Program Initiates New Study

After a transplant surgery, anti-rejection drugs for the organ recipient are a must, but with prolonged use can have serious side effects, including infections, heart disease and cancer.

Now, in a new study, qualifying subjects seeking kidney transplants will receive stem cells from a kidney donor’s bone marrow with the hope of gradually eliminating the need for anti-rejection drugs.

A team led by Joshua Miller, MD, a researcher at Northwestern University’s Feinberg School of Medicine, is working with Northwestern Memorial Hospital’s department of organ transplantation having received a four-year, $2.5 million grant from the National Institutes of Health to enroll 20 patients in the study, which is called "Donor Stem Cells, Campath, T/B Cell Regulation In HLA-Identical Renal Transplants."

If research proves successful, it would mean a dramatic change in the post-transplant quality of life for the transplant recipient.

The study is open only to HLA-identical sibling pairs because these siblings genetically have a more similar set of immunologic markers than a non-related HLA-identical pair. HLA, or human leukocyte antigen, is one of a group of proteins found on the surface of white blood cells and other cells that play an important part in the body's immune response to foreign substances. These antigens vary from person to person, and an HLA compatibility test is performed before organ transplantation to find out if tissues match between a donor and a recipient.

Overall, HLA-identical siblings have very low rejection rates for kidney transplants but until now have still required immunosuppressive drugs to be taken for life.

Stem cells formed in bone marrow are common blood cells from which other specialized blood cells, like immune cells, develop and are considered important to help prevent rejection of the kidney transplant. By transplanting these cells from the kidney donor into the recipient, the study seeks to prove that the stem cells will mature in the recipient’s body and will allow the immune system to recognise the new organ as its own.

The stem cells are infused into the transplant recipient via an IV five days after surgery. The next stem cell transfusion is about three months after surgery, then six months and finally nine months after the transplant. The recipient is treated with Campath-1H, a potent antibody used extensively at Northwestern to prevent rejection, in addition to other standard anti-rejection medications. About a year after surgery, the subject is weaned off of one anti-rejection drug, then another, while undergoing tests to ensure the transplant is still going well.

“This is an exciting area of research which holds a great deal of promise if successful,” says Dr. Abecassis. “We are excited to be the only center in the region offering this to qualifying patients.”


Published January 20, 2008 in the journal Nature Neuroscience
return to top of page


Yale Team Identifies Key Factor in Stress Effects on the Brain

Acute and chronic stress can have devastating effects on the brain, and Yale School of Medicine researchers have pinpointed one receptor that plays a key role in that harmful cycle.

“This could provide new targets for the development of antidepressant medications,” said Ronald Duman, professor of psychiatry and pharmacology and senior author of the study.

Duman said uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and post-traumatic stress disorders, which have been linked to cellular changes in the hippocampus. The hippocampus is a part of the brain that is particularly susceptible to stress.

But little is known about the underlying mechanisms that block the growth of new neurons, which are needed for antidepressants to be effective in treating depression and anxiety.

The researchers discovered in this mouse study that when activated, the receptor for IL-1ß prevents the brain from creating new neurons. It also decreased the animals’ preference for a sweetened solution, a response that mirrors the inability to feel pleasure that people experience with depression.

IL-1ß is a cytokine—or signaling compound—that promotes inflammation. Previous animal studies showed that exposure to stress increases IL-1ß in several brain areas, including the hippocampus. It also has been demonstrated that administering IL-1ß produces several stress-like effects in the hypothalamus, pituitary, and adrenal system as well as the hippocampus.

The team blocked the effects of IL-1ß with an inhibitor, resulting in blockade of cell cycle arrest.

“This is the first study to show how IL-1ß - when activated by acute and chronic stress - arrests the cell cycle,” said Ronald Duman, professor of psychiatry and pharmacology.

Published January 1, 2008 in the PNAS - Proceedings of the National Academy of Sciences
return to top of page


WEDNESDAY - January 23, 2008---------------------------------------------News Archive/Return to Today's News Alerts

Ebola Virus Disarmed by Excising a Single Gene

The deadly Ebola virus, an emerging public health concern in Africa and a potential biological weapon, ranks among the most feared of exotic pathogens.

Due to its virulent nature, and because no vaccines or treatments are available, scientists studying the agent have had to work under the most stringent biocontainment protocols, limiting research to a few highly specialized labs and hampering the ability of scientists to develop countermeasures.

Now, however, a team of researchers from the University of Wisconsin-Madison has figured out a way to genetically disarm the virus, effectively confining it to a set of specialized cells and making the agent safe to study under conditions far less stringent than those currently imposed.

"We wanted to make biologically contained Ebola virus," explains Yoshihiro Kawaoka, a professor of pathobiological sciences in the University of Wisconsin-Madison School of Veterinary Medicine and the senior author of a paper describing the system for containing the virus. "This is a great system."

Taming Ebola virus depends on a single gene known as VP30. Like most viruses, Ebola is a genetic pauper. It has only eight genes and depends on host cells to provide much of the molecular machinery to make it a successful pathogen. The virus's VP30 gene makes a protein that enables it to replicate in host cells. Without the protein, the virus cannot grow.

And Kawaoka, an internationally noted virologist, is convinced of the safety of the new system: "We did this work in a BSL 4, and the altered cells didn't produce any infectious virus after many passages or replication cycles."

"This system can be used for drug screening and for vaccine production," Kawaoka says, noting that getting the equipment and compounds for such work into a BSL 4 lab is extremely difficult. "High throughput screening (for drugs) in a BSL 4 is almost impossible."

But according to Kawaoka, making the agent available for study to a broader cross section of science is essential for thwarting the virus that kills a high percentage of its victims because there is now no defense against it. A new strain of Ebola, which so far has emerged only in remote areas of the world, was recently identified in Uganda and has killed at least 40 people.

"This is an emerging virus and it's highly lethal," Kawaoka says. "But because of the BSL 4 requirement, knowledge of this virus is limited.".

Published January 22, 2008 in the PNAS - Proceedings of the National Academy of Sciences
return to top of page


Brain Connections Strengthen In Waking Hours, Weaken In Sleep

Most people know it from experience: After so many hours of being awake, your brain feels unable to absorb any more-and several hours of sleep will refresh it.

Now new research from the University of Wisconsin-Madison School of Medicine and Public Health (UW-Madison) clarifies this phenomenon, supporting the idea that sleep plays a critical role in the brain's ability to change in response to its environment. This ability, called plasticity, is at the heart of learning.

UW-Madison scientists show by several measures that synapses — nerve cell connections central to brain plasticity — are very strong when rodents are awake and weak when they are asleep.

The researchers believe that people sleep so that their synapses can downsize and prepare for a new day and the next round of learning and synaptic strengthening.

The human brain expends up to 80 percent of its energy on synaptic activity, constantly adding and strengthening connections in response to all kinds of stimulation, explains study author Chiara Cirelli, associate professor of psychiatry.

"We need an off-line period, when we are not exposed to the environment, to take synapses down," Cirelli say. "We believe that's why humans and all living organisms sleep. Without sleep, the brain reaches a saturation point that taxes its energy budget, its store of supplies and its ability to learn further."

To strengthen their case, Cirelli and colleagues performed studies in live rats stimulating one side of each rat's brain with an electrode following waking and sleeping and then measuring the "evoked response," which is similar to an EEG, on another side.

The theory she and collaborator Giulio Tononi, professor of psychiatry, have developed, called the synaptic homeostasis hypothesis, runs against the grain of what many scientists currently think about how sleep affects learning. The most popular notion these days, says Cirelli, is that during sleep synapses are hard at work replaying the information acquired during the previous waking hours, consolidating that information by becoming even stronger.

"That's different from what we think," she says. "We believe that learning occurs only when we are awake, and sleep's main function is to keep our brains and all its synapses lean and efficient."

Published January 20, 2008 in the journal Nature Neuroscience
return to top of page


Nasal Irrigation Flushes Away Kids' Cold Symptoms

Nasal irrigation with a saline solution of processed seawater may clear up children's cold symptoms faster than standard medication alone and prevent them from returning, researchers here found.

Kids' stuffy and runny noses improved more in the first three weeks of treatment when frequent saline rinses were used along with standard medication than with medication alone (P<0.05 for both), reported Ivo Slapak, M.D., of Teaching Hospital Brno, and colleagues.

Perhaps the most compelling result was the reduction in medication use for children who used the low-volume wash, commented Melissa A. Pynnonen, M.D., of the University of Michigan in Ann Arbor, in an interview. But overall evidence of efficacy has been poor, the researchers said. And, it was questionable whether irrigation would be a feasible treatment for children, Dr. Pynnonen said.

"This was really well tolerated," Dr. Pynnonen said. "The question was whether you can get kids to do it, and these authors show that you can."

Their prospective, parallel-group, open-label study included 401 children ages six to 10 seen for uncomplicated cold or flu in eight pediatric outpatient clinics. Participants were randomized to treatment with standard medication, which could include antipyretics, nasal decongestants, mucolytics, and antibiotics, alone or in combination with nasal wash, and then observed over 12 weeks.

The nasal irrigation used was a commercially available product (Europe: Physiomer [In the USA a similar product may be Ocean Complete Sinus Rinse - but always check with your doctor or pharmacist on instructions on how to use]) processed from Atlantic Ocean seawater using electrodialysis to maintain the concentration of trace elements and minerals, the researchers said. Patients used the saline nasal wash in a volume of 3 to 6 mL for each nostril six times a day during acute illness and three times a day for prevention over the remainder of follow-up.

Long-term use of topical decongestants, although common, they said, "can lead to complications, including paranasal sinusitis and histologic changes in the mucosa."

The children had more complaints about the higher volume washes and three patients reported nosebleeds, but overall it was well tolerated, Dr. Šlapak and colleagues said. The study was limited by its unblinded design and use of symptom scores for which a clinically significant level of difference has not been established, the researchers noted.

"It is not clear whether the effect is predominantly mechanical, based on clearing mucus, or whether salts and trace elements in seawater solutions play a significant role," the researchers said. However, the benefit is likely related to more than mucus clearance because it lasted beyond the acute phase of cold or flu, Dr. Pynnonen said. estrogen.

Published January 1, 2008 issue of the Archives of Otolaryngology - Head & Neck Surgery
return to top of page


TUESDAY - January 22, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Mice in Stem-Cell Study Boosting Hopes for Muscular Dystrophy

Using embryonic stem cells from mice, UT Southwestern Medical Center researchers have prompted the growth of healthy - and more importantly, functioning - muscle cells in mice afflicted with a human model of Duchenne muscular dystrophy.

The study represents the first time transplanted embryonic stem cells have been shown to restore function to defective muscles in a model of muscular dystrophy.

The researchers’ newly developed technique, which involves stringent sorting to preserve all stem cells destined to become muscle, avoids the risk of tumor formation while improving the overall muscle strength and coordination of the mice, the researchers found.

The mice used in the study lacked dystrophin, the same protein that humans with the fatal wasting disease also are missing. The study, is headed by Dr. Rita Perlingeiro, assistant professor of developmental biology and molecular biology.

"We envision eventually developing a stem-cell therapy for humans with muscular dystrophy, if we are able to successfully combine this approach with the technology now available to make human embryonic stem cells from reprogrammed skin cells,” Dr. Perlingeiro said. “These cells can be transplanted into the muscle, and they cause muscle regeneration resulting in stronger contractility.”

“The problem had been that embryonic stem cells make everything,” Dr. Perlingeiro said. “They make a great variety of cells. The trick is to pull out only the one type you want.”

The UT Southwestern researchers focused on manipulating genes that are active in the very early stages as embryonic stem cells start to develop into more specialized cells. At first, they activated a gene called Pax3, which is involved in creating muscle cells, and then injected those cells into the animals’ muscles. Those cells caused tumors containing many different types of cells, indicating that there were still residual undifferentiated embryonic stem cells in the cultures at the time of implantation.

The final selection of cells was again injected into the animals’ hind-limb muscles. After a month, fluorescent dyes showed that the cells had deeply penetrated the muscle, an indication that they were growing and reproducing as desired, and many of the muscle fibers also contained dystrophin, the key protein lacking in muscular dystrophy. Tests of isolated muscles showed that the treated muscles were significantly stronger than untreated mice lacking dystrophin, although not quite as strong as those of normal mice.

After three months, the mice also showed no signs of tumors. Tests of isolated muscles showed that the treated muscles were significantly stronger than untreated mice lacking dystrophin, although not quite as strong as those of normal mice. The treated mice also were tested for coordination. Again, their performance was better than that of untreated mice, but not as good as that of normal mice.

Published January 20, 2008 in the journal Nature Medicine
return to top of page


Caffeine Doubles Miscarriage Risk: Study

Pregnant women who drink two or more cups of coffee a day have twice the risk of having a miscarriage as those who avoid caffeine, U.S. researchers said on Monday.

They said the study provides strong evidence that high doses of caffeine during pregnancy - 200 milligrams or more per day or the equivalent of two cups of coffee - significantly increase the risk of miscarriage.

"Women who are pregnant or are actively seeking to become pregnant should stop drinking coffee for three months or hopefully throughout pregnancy," said Dr. De-Kun Li of Kaiser Permanente Division of Research, whose study appears in the American Journal of Obstetrics and Gynecology.

Li said anywhere from 15 to 18 studies have found a link between caffeine use during pregnancy and miscarriage. But that association has been clouded by the fact that many pregnant women avoid caffeine because it makes them nauseated, which could skew the results.

Li and colleagues took pains to control for that possibility. Their study involved 1,063 pregnant women who were members of the Kaiser Permanente health plan in San Francisco from October 1996 through October 1998. Women in the group never changed their caffeine consumption during pregnancy.

What they found was women who consumed the equivalent of two or more cups of regular coffee or five 12-ounce cans of caffeinated soda - were twice as likely to miscarry as pregnant women who avoided caffeine.

This risk appeared to be related to the caffeine, rather than other chemicals in coffee, because they also saw an increased risk when the caffeine was consumed in soda, tea, and hot chocolate.

Published January 21, 2008 in the American Journal of Obstetrics
return to top of page


More Evidence of VTE Risk Added to Birth Control Patch Label

The FDA today announced changes to the label of the norelgestromin/ethinyl estradiol transdermal contraceptive patch (Ortho Evra) to reflect new evidence of a risk for venous thromboembolism.

The updated labeling for the patch suggests that doctors balance the risk for venous thromboembolism and greater exposure to estrogen with the risk for pregnancy if the patch were not used.

The evidence is from an epidemiological study of women ages 15 to 44 conducted by the Boston Collaborative Drug Surveillance Program on behalf of the maker of the patch. The study found that those using the patch were at higher risk for venous thromboembolism than women taking birth control pills.

The agency's action follows the addition to the label of conflicting results from two epidemiological studies in September 2006; one) that women using the patch had about double the risk of nonfatal venous thromboembolic events compared with women taking oral contraceptives and two) that risk was similar with the patch and pills containing 35 mg of ethinyl estradiol and norgestimate.

In 2005, the FDA added information to the Ortho Evra label warning that women using the patch were exposed to 60% more estrogen than women taking pills containing 35 mg of estrogen.

Published January 18, 2008 by the United States Food and Drug Administration
return to top of page


MONDAY - January 21, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Gene Studies Identify Molecular Pathways That Contribute to Acquiring Lupus

Systemic lupus erythematosus, lupus for short, affects at least 1.4 million people in the United States and 50,000 in Britain, advocacy groups say.

It can damage the joints, kidneys, heart, lungs, brain and blood and is marked sometimes by a characteristic butterfly-shaped rash on the face.

Three studies in the journal Nature Genetics and a fourth in the New England Journal of Medicine identify several areas of DNA that carry mutations in people with lupus and their relatives. One international team of researchers studied the DNA of more than 6,700 women, including people with lupus, their relatives, and unrelated people with no evidence of the disease. Among the four studies, about 10,000 people were tested and 13 different genes were implicated.

"Overall, these papers confirm what investigators have been finding over the past decades," said Dr. Mary Kuntz Crow of the Hospital for Special Surgery in New York.

"They show that many aspects of the immune system are involved in the development of the disease, but they also provide a new level of detail regarding the specific molecular pathways that contribute."

Some of the genes also apparently contribute to blood vessel function and some have unknown roles, the researchers said.

"In the major studies, all of the subjects were of European descent, but lupus is most severe in people with African, Asian and Hispanic backgrounds," Crow said in a statement.

"We need to confirm that these same genes are involved in all of our patient populations and identify any distinct genes that might be involved in those populations at greatest risk for poor outcomes."

Published January 20, 2008 in the journal Nature Genetics:
A nonsynonymous functional variant in integrin-M (encoded by ITGAM) is associated with systemic lupus erythematosus

Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Published January 20, 2008 in the New England Journal of Medicine: Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX

return to top of page


Discovery of 'Creator' Gene for Cerebral Cortex Points to Potential Stem Cell Treatments

University of California, Irvine researchers have identified a gene that is specifically responsible for generating the cerebral cortex, a finding that could lead to stem cell therapies to treat brain injuries and diseases such as stroke and Alzheimer’s.

Dr. Edwin Monuki, doctoral student Karla Hirokawa and their colleagues in the departments of Pathology & Laboratory Medicine and Developmental & Cell Biology found that a gene called Lhx2 serves as the long-sought cortical “creator” gene that instructs stem cells in the developing brain to form the cerebral cortex. This portion of the brain is responsible for higher sensory and cognitive functions, such as language, decision-making and vision. Without this gene, cortical cells will not form.

“This new understanding of Lhx2’s role in cortical development can potentially be used in stem cell research efforts to grow new cortical neurons that can replace damaged ones in the brain,” said Monuki, an assistant professor of pathology. “This finding has implications for continuing efforts to help people recover from a stroke or slow the progress of neurodegenerative diseases.”

Lhx2 is among a group of genes – called selector genes – that act during key moments of embryonic and fetal development, directing stem cells to grow into specific parts of the body – such as brain, blood and bone.

In tests on rodents, the researchers found that Lhx2’s cortical selector activity is critical only during the stage when the developing cortex is made up of stem cells, not before or after. In addition, they found that cortical stem cells that don’t express the Lhx2 gene turn into a different cell type – called a hem cell – that induces neighboring cells to become the hippocampus, the oldest part of the cortex in evolutionary terms and a major memory center of the brain.

Lhx2’s role in cerebral cortex development has far-reaching implications in the nascent field of stem cell research. The Monuki lab is currently studying how to activate Lhx2 genes in neural stem cells and initiate the process in which new cortical cells can grow. “If successful, the concept of using Lhx2 to instill stem cells with cortical properties could be a basis of clinical studies that could one day help treat patients,” he said.

Researchers in Monuki’s lab are deeply involved with stem cell research. Last month, they published a study identifying a new way to sort stem cells that should be quicker, easier and more cost-effective than current methods. The technique could in the future expedite therapies for people with conditions ranging from brain and spinal cord damage to Alzheimer’s and Parkinson’s diseases.

Published January 18, 2008 in the journal Science
return to top of page


Mediterranean Diet During Pregnancy "Prevents" Child's Asthma and Allergy

Declarative statements from scientists are very rare. A reputation and career can be ruined by over stated results. But most of us prefer a simple explanation for conplicated data. So, the UK's National Health Service (NHS) takes current headlines, reads the data and gives their own evaluation of the science.

The "Mediterranean Diet" has recently been credited with eliminating asthma in children born to mothers who ate no red meat while pregnant. The NHS has come to another opinion after reading the data and is less inclined to draw the same conclusions as the public press, or even the scientists involved.

"Although the exact method is unclear, it seems that mother’s diet during pregnancy was only assessed six and a half years later at the same time that the study was assessing the child’s diet. It is unlikely that mothers remembered exactly what they had eaten during their pregnancy, particularly when information was being collected on such a large number of food items.

Another problem they found was that children who had a clinical diagnosis of asthma were not included in the study. "The study uses some weak methods and the newspapers have overstated the relationship between a mother’s diet during pregnancy and asthma-like symptoms in her children." reports the NHS.

Published January 15, 2008 in the journal Thorax: Mediterranean Diet in pregnancy protective for wheeze and atopy in childhood

Published January 15, 2008 on MedPage Today: Mediterranean Diet During Pregnancy Prevents Child's Asthma and Allergy

Published January 15, 2008 on National Health Service - Choices: Mediterranean diet ‘prevents’ asthma
return to top of page